Discovery of a novel broad-spectrum antifungal agent derived from albaconazole

Article abstract of DOI:10.1021/ml300429p

Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed preliminary in vivo antifungal efficacy in a mice model of systemic candidiasis.

Full text of DOI:10.1021/ml300429p

Letter
pubs.acs.org/acsmedchemlett
Discovery of a Novel Broad-Spectrum Antifungal Agent Derived from
Albaconazole
Remi Guillon,† Fabrice Pagniez,*,‡ Carine Picot,‡ Damien Hedou,§ Alain Tonnerre,† Elizabeth Chosson,§
́
́
Muriel Duflos,† Thierry Besson,§ Cedric Loge,*,† and Patrice Le Pape‡
́
́
†Universite
du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France
‡Universite
de Nantes, Nantes Atlantique Universites, Laboratoire de Parasitologie et Mycologie Medicale, Cibles et Med
Infections et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France
§Universite
de Rouen, Laboratoire C.O.B.R.A., CNRS UMR 6014 & FR 3038, Institut de Recherche en Chimie Organique Fine
(I.R.C.O.F.), rue Tesniere, 76130 Mont Saint-Aignan, France
́ ́ ́ ́
de Nantes, Nantes Atlantique Universites, Laboratoire de Chimie Therapeutique, Cibles et Medicaments des Infections et
́
́
́
́
icaments des
́
̀
S
* Supporting Information
ABSTRACT: Synthesis of a strict structural analogue of
albaconazole in which the quinazolinone ring is fused by a
thiazole moiety led to the discovery of a new triazole with
broad-spectrum antifungal activity. Compound I exhibited high
in vitro activity against pathogenic Candida species and
filamentous fungi and showed preliminary in vivo antifungal
efficacy in a mice model of systemic candidiasis.
KEYWORDS: Candida, Aspergillus, zygomycetes, antifungal agents, azoles, thiazolo[4,5-g]quinazolin-8(7H)-one
zoles (fluconazole, itraconazole, voriconazole, and pos-
Aaconazole) are important drugs for the treatment of
invasive fungal infections (IFIs), which continue to be a major
cause of morbidity and mortality in immunocompromised or
severely ill patients.1 These compounds target the biosynthesis
of ergosterol by inhibiting the cytochrome P450-dependent
lanosterol 14α-demethylase (Erg11p, CYP51), encoded by the
ERG11 gene, resulting in accumulation of toxic methylsterols in
membranes that may culminate in fungistatic effect or fungal
death.2 Most azoles are orally active, show a broad-spectrum
against most yeasts and filamentous fungi, and are relatively
nontoxic. Unfortunately, the increasing number of fungal
infections, coupled with emerging resistance, has resulted in a
need to develop new, more effective agents. Among these
molecules, albaconazole (UR-9825, Palau Pharma S.A., Figure
1)3 is a new oral triazole antifungal agent with broad-spectrum
antifungal activity against resistant and emerging pathogens as
Figure 1. General structures of synthesized compounds.
compared with fluconazole and itraconazole, good pharmaco-
kinetics, and excellent oral bioavailability.4 It has demonstrated
program focused on the synthesis and SAR studies of novel
broad-spectrum antifungal agents,6−10 we aimed to develop a
high in vitro activities against pathogenic yeasts, dermatophytes,
strict structural analogue of albaconazole in which the
quinazolinone ring will be replaced by a thiazoloquinazolinone
scaffold (compounds I and II, Figure 1) via Appel salt
chemistry. Our goal was to slightly increase the size of the
inhibitor to cover a larger area within the active site of fungal
and other filamentous fungi and has been shown to be effective
in animal models of systemic aspergillosis, candidiasis,
cryptococcosis, and scedosporiosis.4 Albaconazole has been
assayed in several clinical trials, including phase I/II studies in
candidal vulvovaginitis, tinea pedis, and onychomycosis
(clinicaltrials.gov: NCT00199264, NCT00509275, and
NCT00730405). However, phase III studies are not available
until now, and the lack of an intravenous form makes studies in
the acute infection setting very difficult.5 As part of our research
Received: November 30, 2012
Accepted: January 17, 2013
© XXXX American Chemical Society
A
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a
Scheme 1. Synthesis of Compound 9
a
Reagents and conditions: (a) H2NCHO, InCl3, 150 °C (mW), 40 min, 81%. (b) HNO3, H2SO4, 100 °C, 1 h, 76%. (c) NaH, benzyl bromide, DMF,
80 °C (mW), 30 min, 84%. (d) Fe, AcOH, EtOH, reflux, 1 h, 93%. (e) Appel salt, CH2Cl2, pyridine, rt, 3 h, 58%. (f) AlCl3, toluene, 65 °C, 30 min,
90%. (g) CuI, pyridine, 115 °C (mW), 15 min, 86%. (h) HBr (48%), 115 °C (mW), 30 min, 93%.
a
Scheme 2. Synthesis of Compound 14
a
Reagents and conditions: (a) AlCl3, toluene, 65 °C, 30 min, 85%. (b) CuI, pyridine, 115 °C (mW), 15 min, 72%. (h) HBr (48%), 115 °C (mW), 30
min, 95%.
a
Scheme 3. Synthesis of Compounds I and II
a
Reagents and conditions: (a) Thiazolo[4,5-g]quinazolin-8(7H)-one (9) or thiazolo[5,4-f]quinazolin-9(8H)-one (14), K2CO3, N-methyl-2-
pyrrolidone, 80 °C, 3 days, 45−47%.
CYP51 while improving calculated logP values (clogP) as
compared to the parent molecule (compound I: clogP = 1.44;
albaconazole: clogP = 2.15; BioByte, Bio-Loom). In addition,
we wanted to check the effect of the position of the thiazole
ring on the biological antifungal activities.
Fusion of the thiazole ring onto the quinazoline moiety was
realized by a thermolysis procedure at 115 °C, in the presence
of copper(I) iodide (CuI), in pyridine (compound 8).
Decyanation (via hydrolysis and decarboxylation) of the
thiazolo-2-carbonitrile ring was performed using 48% hydro-
bromic acid under microwave irradiations to give compound 9.
Scheme 2 outlines the synthesis of thiazolo[5,4-f]quinazolin-
9(8H)-one (14), which was already prepared from 2-amino-5-
nitrobenzoic acid (10) by Besson and co-workers.14−16 The
main difference consisted of the debenzylation of compound 11
before the formation of the thiazole ring as described in
Scheme 1. Finally, thiazoloquinazolinones 9 and 14 were
condensed onto the previously described chiral oxirane 15
[synthesized in seven steps from (R)-methyl lactate]17 in the
presence of K2CO3 in N-methyl-2-pyrrolidone (NMP) at 80 °C
to afford the expected compounds I and II in 47 and 45% yield,
respectively (Scheme 3).
Scheme 1 outlines the synthesis of original 1,3-thiazolo[4,5-
g]quinazolin-8(7H)-one (9) started from 4-bromo-2-nitro-
benzoic acid (1), which reacted with formamide, in the
presence of indium(III) chloride,11 under microwave irradi-
ations, to give 7-bromo-3H-quinazolin-4-one (2) in 81% yield.
Nitration of 2 with a mixture of nitric acid and sulfuric acid at
100 °C afforded compound 3 in 76% yield,12 which was N-
benzylated in position 3 of the quinazolin-4-one skeleton by
reaction with sodium hydride and benzyl bromide in anhydrous
DMF (compound 4). Subsequent reduction of the nitro group
was accomplished with iron/acetic acid in refluxing ethanol13 to
give the corresponding amine 5 (yield 93%). This compound
was then condensed with 4,5-dichloro-1,2,3-dithiazolium
chloride (Appel salt) in dichloromethane at room temperature,
followed by the addition of pyridine, to give the intermediate
imino-1,2,3-dithiazoloquinazolinone 6 in 58% yield. Debenzy-
lation was carried out using aluminum chloride (AlCl3) in
toluene at 65 °C, leading to compound 7 in excellent yield.
In vitro antifungal activities of compounds I and II against
Candida species (yeasts) and filamentous fungi (molds) were
compared with those of fluconazole, voriconazole, itraconazole,
and albaconazole. Evaluations against Candida spp. and
Aspergillus fumigatus strains were realized by Le Pape’s
previously reported method18 and those against other
B
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ACS Medicinal Chemistry Letters
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filamentous fungi according to the CLSI Broth Microdilution
Susceptibility Method (M38).19 The MICs of compounds I and
II and reference drugs are summarized in Tables 1 and 2.
Against the fluconazole-suceptible C. albicans CAAL93 and
CAAL97 isolates (Table 1), compounds I and II displayed a
high level of activity with MIC values ranging from of 0.001 to
0.011 μg mL−1, comparable to voriconazole and albaconazole
values. These compounds were further evaluated against
DSY735 and DSY292 fluconazole-resistant isolates. DSY735
exhibited a gain of function mutation in TAC1 (transcriptional
activator of CDR genes) responsible for Cdr1/2p transporter
overexpression and a presence of the isochrome 5L leading to
higher copy numbers of TAC1 and ERG11 on chromosome
5.20 DSY292 showed a gain of function mutation in MRR1
(transcriptional activator of CaMDR1 gene) and Y132H,
G464S, and R467K amino acid substitutions on CYP51.21
Compound I exhibited high antifungal activities similar to those
of voriconazole and slightly inferior to those of albaconazole,
showing that this compound could overcome overexpression of
efflux pumps and Erg11p (CYP51) but also some specific point
substitutions in the CYP51 enzyme. However, against the
DSY292 isolate, albaconazole appears to be less affected by the
G464S and R467K mutations, which are close to the position of
the fifth heme ligand (Cys470), than either voriconazole or
compound I. This could be explained by tighter affinity and/or
favorable compensatory adjustments of albaconazole within the
active site, even if besides this argument on the CYP51 active
site, we cannot discard either a possible slight increase in
MDR1 efflux for voriconazole and compound I as opposed to
albaconazole. On the other hand, a significant broad-spectrum
antifungal activity was also observed for compound I against C.
krusei, C. glabrata, and C. parapsilosis isolates with MIC values
ranging from <0.005 (for CAKR8) to 0.182 μg mL−1 (for
CAKR7), confirming its interest for fluconazole low-susceptible
strains and fluconazole intrinsically resistant Candida species. In
particular, for the acquired-resistant C. parapsilosis CAPA1 and
CAPA2 isolates, compound I was almost as active as
albaconazole and 7−70-fold more active than voriconazole.
Compound II has a narrow spectrum of activity with a high
level of potency against C. glabrata and C. parapsilosis strains
(MICs ranging from 0.001 to 0.095 μg mL−1) but not against
C. krusei strains (MICs > 2.5 μg mL−1).
The antifungal activities of compounds I and II and reference
drugs against clinical filamentous fungal isolates are shown in
Table 2. A. fumigatus, the most frequent agent of invasive fungal
infections in immunocompromised patients,22 and some
emerging non-Aspergillus molds such as Scedosporium sp.
(SCSP1) and zygomycetes (Rhizomucor pulsillus RHPU1 and
Rhizomucor miehei RHMI1) were used in this study.
Compound I was active against A. fumigatus isolates susceptible
(ASFU7) or resistant to itraconazole (ASFU13, ASFU17,
ASFU19, ASFU20, and ASFU23), with MIC values ranging
from 0.27 (for ASFU23) to 4.5 μg mL−1 (for ASFU20), which
were comparable to those of albaconazole and slightly superior
to those of voriconazole, the first-line agent for the treatment of
invasive aspergillosis.23 Because compound II was not active
against azole-susceptible ASFU7, this compound was not
evaluated against the other filamentous fungi. Against the
emerging fungi (SCSP1, RHPU1, and RHMI1), compound I
exhibited also MIC values (1−2 μg mL−1) globally close to
those observed for albaconazole and voriconazole.
The mechanism of action was investigated by studying
inhibition of C. albicans CAAL93 ergosterol biosynthesis after
C
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ACS Medicinal Chemistry Letters
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Table 2. Susceptibilities of Clinical Isolates of Filamentous Fungi to Compounds I and II and Reference Antifungal Agents
a
MIC values (μg mL−1
)
b
b
b
compds
ASFU7
ASFU13
ASFU17
ASFU19 ASFU20
ASFU23
SCSP1
RHPU1
RHMI1
I
0.28 0.01
>43
3.1
1
2.2 0.2
NT
2.1 0.1
NT
4.5
2
0.27 0.02
NT
1
1
2
II
NT
NT
NT
NT
0.125
0.5
NT
NT
2
NT
NT
8
itraconazole
voriconazole
albaconazole
0.42 0.04
0.15 0.01
0.23 0.01
>71
<0.35
>71
>71
>71
<0.35
>71
0.25 0.3
2.1 0.1
3.0 0.3
0.18 0.01
0.22 0.01
1.1 0.3
2.0 0.1
1.2 0.3
0.5
1
a
b
Values represent the mean SD of experiments performed in triplicate. MICs were determined by the M38 method from the CLSI, and each test
was performed twice. A. fumigatus (ASFU7, ASFU13, ASFU19, ASFU20, and ASFU23), Scedosporium sp. (SCSP1), Rhizomucor pusillus (RHPU1),
and Rhizomucor miehei (RHMI1). NT = not tested.
treatment by compound I. As shown in Table 3, at the
body weight of compound I or albaconazole solubilized in 5%
DMSO for 5 consecutive days. The control group received 100
μL of 0.9% saline solution with 5% DMSO. The efficacy of the
compound I and albaconazole was expressed as the survival
rates 13 days after infection. On day 13 after infection, 75 and
87% of mice were still alive in compound I and the
albaconazole groups, respectively, while all control mice died
on day 5, demonstrating a high and significant (p < 0.001, Log
rank test) efficacy against murine invasive candidiasis and
suggesting a possible action of this compound against other
invasive fungal infections.
In summary, we have synthesized a novel antifungal agent
derived from albaconazole with broad-spectrum in vitro
antifungal activity against pathogenic Candida species and
filamentous fungi, including clinical isolates that are resistant to
fluconazole and itraconazole. This new CYP51 inhibitor also
displayed preliminary in vivo antifungal efficacy in a mice model
of systemic candidiasis. All of the biological results are close to
those observed for voriconazole or albaconazole. This work
confirms the promising interest of a new azole compound
bearing an original fused tricyclic scaffold. Moreover, we can
expect that its lower clogP value as compared to the parent
molecule could modulate the characteristics of this albacona-
zole-derived compound on either various types of invasive
fungal infections or the route of administration. Further
optimizations are ongoing, and the results will be reported in
due course.
concentrations of 4.5 and 22.0 ng mL−1, surrounding the MIC
Table 3. Effect of Compound I on the Sterol Composition of
C. albicans CAAL93
compd I (ng mL−1
)
a
sterols
lanosterol
control
4.5
22.0
9.2
0.3
29.9
4.4
41.6
20.4
eburicol
zymosterol
episterol
fecosterol
8.9
2.0
13.0
9.1
2.9
14-methyfecosterol
14-methylepisterol
14-methyl-3,6-diol
ergosterol
3.8
5.9
11.4
15.7
5.4
55.3
51.1
5.4
a
Sterols of interest were identified by their mass spectrum. The area
under curve (AUC) of each peak was used to calculate a ratio: sterol
AUC/sum of sterols AUC. Values are the result of one experiment.
value (11.0 ng mL−1), compound I inhibited ergosterol
biosynthesis in a dose-dependent manner, while lanosterol,
eburicol, and methylated sterols at C14 position accumulated,
confirming an inhibition of the C. albicans CYP51 enzyme.
Finally, we compared the in vivo activity of compound I with
that of albaconazole against a lethal systemic infection in mice
caused by C. albicans (Figure 2). This study will be considered
in more detail elsewhere.
Transiently neutropenic swiss mice (CE Janvier, Le Genest
St. Isle, France) were injected intravenously with fluconazole-
susceptible C. albicans (CAAL93) blastoconidia. One hour after
infection, mice were treated per os once daily with 15 mg/kg
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures for assay protocols, synthesis, and
characterization of compounds I and II. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +33(0)240 412 828. Fax: +33(0)240 412 866. E-mail:
fabrice.pagniez@univ-nantes.fr (F.P.). Tel: +33(0)240 411 108.
Fax: +33(0)240 412 876. E-mail: cedric.loge@univ-nantes.fr
(C.L.).
Funding
R.G. and D.H. acknowledge the Minister
Superieur et de la Recherche (MESR) for their Ph.D. grants.
Notes
̀
e de l’Enseignement
́
Figure 2. Effects of compound I and albaconazole against systemic
infection caused by C. albicans (CAAL93) in neutropenic mice (n = 8).
The authors declare no competing financial interest.
D
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ACS Medicinal Chemistry Letters
Letter
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ACKNOWLEDGMENTS
■
We thank Pr. Dominique Sanglard (Institute of Microbiology,
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